For the first time, a systematic, team approach to the development of superior new anthracyclines is proposed. In an integrated, multidisciplinary program, synthesis of new structures will be based on a) unique lead compounds that have shown significantly reduced cardiotoxic effects and deletions of certain DNA interactions, and b) replacement of glycosidic O with CH2 to avoid rapid metabolic deactivation. The lead structures are 5-iminodaunorubicin, the only known anthracycline modified at the quinone, and the non-DNA interactive N,N-dibenzyldaunorubicin. Antitumor screening of new compounds will be combined with studies of DNA interactions, tests for cardiotoxicity based on electrocardiographic changes in the rat, and studies of nucleolar ultrastructure changes in the rat heart--possibly as independent markers of cardiotoxicity. Because the quinone function is a key site of biological action, and redox properties are important, studies of metabolic disposition will begin with measurement of enhanced O2 cycling in liver microsomes. Besides these studies using subcellular systems, we will determine metabolism of new compounds in hepatocytes, liver perfusion systems and in intact rats. Because of the existing background in the various separate disciplines not previously brought together, and with SRI's unique lead compounds, the team approach has an excellent chance of success, that can lead to a major impact on therapy.